Hypocalcemia Is Associated With Disease Severity in Patients With Dengue
Hypocalcemia Is Associated With Disease Severity in Patients With Dengue
Hypocalcemia Is Associated With Disease Severity in Patients With Dengue
Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
3
Ministry of Health Care and Nutrition, Colombo, Sri Lanka
2
Abstract
Introduction: Dengue hemorrhagic fever (DHF) is a major cause of morbidity and mortality in tropical regions. Serum free calcium (Ca 2+) is
known to be important in cardiac and circulatory function. We evaluated association between serum Ca2+ level and severity of dengue.
Methodology:A cross-sectional study was carried out at a tertiary care private hospital in Sri Lanka. A probable case of dengue was
diagnosed and classified according to World Health Organization criteria and confirmed by either IgM antibody, PCR, or NS1 antigen
detection. Socio-demographic details were collected using an interviewer-administered questionnaire.
Results: The sample size was 135. The mean age was 26.1 years, and the majority were males (n = 80, 59.3%). DHF was diagnosed in 71
patients (52.6%). Mean serum Ca2+ level of the study population was 1.05 mmol/L (range 0.771.24). Mean serum Ca2+ was significantly
higher in patients with dengue fever (DF) (1.09 mmol/L) than in those with DHF (1.02 mmol/L) (p < 0.05). A significant difference was
observed between mean serum calcium levels of DHF I and DHF II. Prevalence of hypocalcemia in DHF and DF patients was 86.9% (n =
60) and 29.7% (n = 11), respectively (p < 0.05).
Conclusions: Serum Ca2+ levels significantly correlated with dengue severity. Serum Ca2+ levels were significantly lower and hypocalcemia
was more prevalent in patients with DHF than in patients with DF. Further studies are required to determine whether hypocalcemia can be
utilized as a prognostic indicator and to evaluate effectiveness of calcium therapy in prevention of dengue complications.
Introduction
Dengue is a disease spread by the Aedes mosquito,
and it is an entity known to mankind since 1780 [1].
After 1960, the incidence of dengue has shown an
exponential increase, with several recent outbreaks
reported mainly from South Asian countries [2].
Nearly 70% of the worlds population at risk of
dengue lives in the Southeast Asian and Western
Pacific regions [2]. Dengue infection and dengue
hemorrhagic fever (DHF) are major causes of
morbidity and mortality in the tropical regions of the
world [3]. It is estimated that 390 million become
infected with dengue per year, of which 96 million
manifest apparently [4]. Due to this high prevalence
and considerable mortality, over the last few years
there has been a heightened interest in disease
prevention and effective strategies for management.
However, at present, the pathogenesis of dengue and
its complications are not completely understood. The
dengue virus is a single-stranded RNA virus of the
Definitions
A probable case of dengue was diagnosed
according to the World Health Organization (WHO)
criteria [15]. Confirmation of diagnosis was done with
one of the following laboratory tests: IgM antibody
(MAC-ELISA) (PANBIO diagnostics, Brisbane,
Australia), dengue virus RT-PCR (single tube
multiplex RT-PCR was carried out according to the
standard method described previously [16]), or serum
dengue NS1 (non-structural protein 1) antigen
detection (PLATELIA TM Dengue NS1 Ag assay
[BIORAD, Marnes-la-coquette, France]). DHF was
diagnosed and classified in to four stages (DHF I-IV)
according to the WHO criteria as follows: DHF I
positive tourniquet test and/or easy bruising; DHF II
presence of spontaneous bleeding manifestations;
DHF III circulatory failure (rapid, weak pulse and
narrow pulse pressure or hypotension); and DHF IV
profound shock with undetectable pulse and blood
pressure. The prevalence of myocarditis and its
correlation with dengue severity was also analyzed.
Myocarditis was diagnosed either by the presence of
changes in the 12-lead ECG (ST segment, T inversion
or right bundle branch block) or by the twodimensional echocardiogram (2D-echo) findings
(hypo-kinetic segments).
Data collection and analysis
Socio-demographic details were collected using an
interviewer-administered structured questionnaire. The
clinical parameters recorded were presence of
suggestive symptoms (fever, headache, retro-orbital
pain, arthralgia, myalgia, rash, and bleeding
manifestations), evidence of fluid leakage (pleural
effusion and ascitis), pulse rate, and systolic and
diastolic blood pressure. In addition, the following
investigations were performed: white cell count,
platelet count, packed cell volume, serum free calcium
level, ECG, and 2D echo. Blood samples for the
estimation of serum calcium were drawn between days
5 and 10 of the fever. Hypocalcemia was defined as
the presence of a serum free calcium level of < 1.1
mmol/L. All data were double-entered and crosschecked for consistency. Data were analyzed using
SPSS version 14 (SPSS Inc., Chicago, IL, USA)
statistical software package. The significance of the
differences between proportions (%) and means were
tested using the z-test and students t-test or ANOVA,
respectively.
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Results
The sample size was 135, and the mean age was
26.1 years (range 665 years). The majority of the
patients were males (n = 80, 59.3%), and only 4
patients (3%) had a previous history of laboratoryconfirmed dengue infection. The diagnosis was
confirmed by using the dengue NS1 antigen, PCR, or
IgM in 65 (48.1%), 1 (7.4%), and 39 (28.9%) patients,
respectively. DHF was diagnosed in 71 patients
(52.6%), of which 3 (4%) had DHF I, 34 (47.8%) had
DHF II, and 29 (40.8%) had DHF III. There were no
patients with DHF IV in the present cohort, and all
patients recovered completely.
Complete data on serum free calcium was
available only in 107 patients. The mean serum free
calcium level of the study population was 1.05
mmol/L (range 0.771.24). The mean serum free
calcium was significantly higher in patients with DF
(1.09 mmol/L) than in those with DHF (1.02 mmol/L)
(p < 0.05). The mean serum free calcium levels in the
different stages of DHF were: DHF I 1.076 mmol/L;
DHF II 1.022 mmol/L; and DHF III 1.033. A
significant difference was observed between DHF I
and DHF II. Prevalence of hypocalcemia in DHF
patients was 86.9% (n = 60), whereas it was 29.7% (n
= 11) in patients with DF (p < 0.05).
Two-dimensional echo findings were available for
37 patients; no abnormalities were detected in 27
patients (72.9%). Features of myocarditis were present
in 21.6% (n = 8) of patients, all of whom were in the
DHF group. However, only 4 out of the above 8
patients had an ejection fraction of less than 60%.
Dys-synchronic movements in ventricles were
observed in 1 patient. ECGs were available in 51
patients, of which 80.4% (n = 41) had no abnormality.
The commonest abnormality noted was T inversion in
right or/and left leads, which was present in 9 (17.6%)
patients. A right bundle branch block was present in 1
patient. QT changes and ST segment changes were not
observed in the study population. Evidence of
myocarditis (ECG and/or 2D echo) was seen in 16
patients, of which 14 (87.5%) were in the DHF group
and 2 were in the DF group (12.5%) (p < 0.05).
Discussion
Dengue is the most prevalent mosquito-borne viral
infection in the world [17]. Each year, there are 50
million dengue infections and 500,000 individuals
are hospitalized with DHF, mainly in Southeast Asia,
the Pacific, and the Americas [18]. Sri Lanka is a
middle-income developing country in the South Asian
region with a population of over 20 million. It is an
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Corresponding author
Dr. Godwin R. Constantine (MBBS, MD)
Consultant Cardiologist/Senior Lecturer
Department of Clinical Medicine, Faculty of Medicine
University of Colombo, Sri Lanka
Phone: + 94 777 575683
Email: grogerconstantine@gmail.com
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